Enlarged-hetero-ring prostacylin analogs

ABSTRACT

Prostaglandin (PG 1 ) derivatives having (1) a 6-keto feature, together with a 9-deoxy-9-hydroxymethyl feature for example ##STR1## or (2) a 9-deoxy-6,9-epoxymethano feature together with a 5-halo or 6-hydroxy feature, for example ##STR2## or a 5,6-didehydro feature, for example in an enol ether of the formula. ##STR3## said derivatives having pharmacological activity. Processes for preparing them and the appropriate intermediates are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a division of application Ser. No. 819,941, filed July 28, 1977 now issued as U.S. Pat. No. 4,124,599 which is in turn a continuation-in-part of copending application Ser. No. 725,547 filed Sept. 22, 1976, now abandoned which was a continuation-in-part of then copending application Ser. No. 716,771 filed Aug. 23, 1976, since abandoned.

BACKGROUND OF THE INVENTION

This invention relates to prostaglandin derivatives and to a process for preparing them.

The prostaglandins and analogs are well-known organic compounds derived from prostanoic acid which has the following structure and atom numbering: ##STR4##

As drawn hereinafter the formulas represent a particular optically active isomer having the same absolute configuration as PGE₁ obtained from mammalian tissues.

In the formulas, broken line attachments to the cyclopentane ring or side chain indicate substituents in alpha configuration, i.e. below the plane of the ring or side chain. Heavy solid line attachments indicate substituents in beta configuration, i.e. above the plane.

For background on prostaglandins, see for example Bergstrom et al., Pharmacol, Rev. 20, 1 (1968). For related compounds see Pace-Asciak et al., Biochem. 10, 3657 (1971). Related compounds are described in a publication on 6-keto-prostaglandin F₁α by Pace-Asciak, J. Am. Chem. Soc. 98, 2348 (1976) and a publication on "PGX" (6,9α-oxido-9α,15α-dihydroxyprosta-(Z)5, (E)13-dienoic acid) by E. J. Corey et al., J. Am. Chem. Soc. 99, 20006 (1977).

Some of the compounds of this invention may be regarded as analogs of prostacyclin and prostacyclin-type compounds.

Prostacyclin, an organic compound related to prostaglandins, is (5Z)-9-deoxy-6,9α-epoxy-Δ⁵ -PGF₁ and is represented by the formula ##STR5## For its synthesis and structure see for example R. A. Johnson et al., J. Am. Chem. Soc. 99, 4182 (1977) and Prostaglandins 12, 915 (1976), and E. J. Corey et al., cited above. For some of its biological properties and uses see the references cited in the Johnson references. Prostacyclin is referred to as "PGI₂ ", see Anonymous, Prostaglandins 13, 373 (1977).

The essential material for this application, including the background of the invention, the disclosure of the invention, and the description of the preferred embodiments, including Preparations and Examples, is incorporated by reference from U.S. Pat. No. 4,124,599 columns 1-69 , inclusive, under the provisions of M.P.E.P. 608.01(p).

SUMMARY OF THE INVENTION

It is the purpose of this invention to provide novel products having pharmacological activity. It is a further purpose to provide processes for preparing these products and their intermediates.

Accordingly, there is provided a compound of the formula: ##STR6## or a mixture comprising that compound and the enantiomer thereof wherein R₂₀ is ##STR7## wherein L is

(1) --(CH₂)_(d) --C(R₂)₂ --

(2) --CH₂ --O--CH₂ --Y-- or

(3) --CH₂ CH═CH--

wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, being the same or different with the proviso that one R₂ is not methyl when the other is fluoro, and Y is a valence bond, --CH₂ -- or --(CH₂)₂ --,

wherein

Q is ##STR8## wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive,

wherein

R₁ is

(1) --COOR₃

(2) --CH₂ OH

(3) --CH₂ N(R₉)(R₁₈) ##STR9## wherein R₃ is (a) hydrogen, (b) alkyl of one to 12 carbon atoms, inclusive, (c) cycloalkyl of 3 to 10 carbon atoms, inclusive, (d) aralkyl of 7 to 12 carbon atoms, inclusive, (e) phenyl, (f) phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, ##STR10## wherein R₁₀ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, and wherein R₁₁ is hydrogen or benzoyl, or (n) a pharmacologically acceptable cation, wherein R₉ is hydrogen, methyl, or ethyl, and R₁₈ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with alkyl of one to 4 carbon atoms, inclusive;

wherein R₄ is ##STR11## wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ -- and terminal methyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R₅ nor R₆ is fluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--) or C_(j) H_(2j) wherein C_(j) H_(2j) is a valence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between CR₅ R₆ - and the phenyl ring; wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ -- wherein R₇ is alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2 or 3, with the proviso that not more than two T's are other than alkyl and when s is 2 or 3 the T's are either the same or different; and

wherein

X is

(1) trans--CH═CH--

(2) cis--CH═CH--

(3) --C═C-- or

(4) --CH₂ CH₂ --;

including the lower alkanoates thereof.

In formula IV as used herein, attachment to R₂₀ corresponds to bonds to the cyclopentane ring at the C-8, C-9, and C-12 positions following prostaglandin nomenclature, thus: ##STR12##

Within the scope of the prostaglandin derivatives described herein there are represented

(a) PGF.sub.α compounds when R₂₀ is ##STR13## (b) 11β-PGF.sub.α compounds when R₂₀ is ##STR14## (c) 11-Deoxy-11-keto-PGF.sub.α compounds when R₂₀ is ##STR15## (d) 11-Deoxy-11-methylene-PGF.sub.α compounds when R₂₀ ##STR16## (e) 11-Deoxy-PGF.sub.α compounds when R₂₀ is ##STR17## (f) 11-Deoxy-10,11-Didehydro-PGF.sub.α compounds when R₂₀ is ##STR18## (g) 11-Deoxy-11-hydroxymethyl-PGF.sub.α compounds when R₂₀ is ##STR19## 3-Oxa-16-(m-chlorophenoxy)-17,18,19,20-tetranor-cis-13-; 3-Oxa-(p-fluorophenoxy)-17,18,19,20-tetranor-cis-13-;

3-Oxa-16-phenoxy-18,19,20-trinor-cis-13-;

3-Oxa-16-methyl-16-phenoxy-18,19,20-trinor-cis-13-;

Likewise following the procedures of Examples 11, 12, and 15, but employing corresponding starting materials, there are obtained the formula -I, -II, -III, and -IV compounds, namely

9-deoxy-9α-hydroxymethyl-6-keto-PGF₁ -,

9-deoxy-6ξ,9α-epoxymethano-6ξ-hydroxy-PGF₁ -.

5ξ-halo-9-deoxy-6ξ,9α-epoxymethano-PGF₁ -, and

(5Z)-9-deoxy-6,9α-epoxymethano-Δ⁵ -PGF₁ -type compounds, in methyl ester form wherein R₁ is --COOCH₃, having the following structural features:

2,3-Didehydro-;

2,2-Dimethyl-;

2a,2b-Dihomo-;

4-Oxa-4a-homo-;

11-Deoxy-10,11-didehydro-;

11β-;

11-Deoxy-11-keto-;

11-Deoxy-;

11-Deoxy-11-methylene-;

11-Deoxy-11-hydroxymethyl-;

15β-;

15-Keto-;

15-Deoxy-;

15-Methyl-15(S)-;

15-Methyl-15(R)-; and

17,18-Didehydro-. 

I claim:
 1. A 5Z compound of the formula ##STR20## wherein R₂₀ is ##STR21## wherein L is(1) --(CH₂)_(d) --C(R₂)₂ -- (2) --CH₂ --O--CH₂ --Y-- or (3) --CH₂ CH═CH--wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, being the same or different with the proviso that one R₂ is not methyl when the other is fluoro, and Y is a valence bond, --CH₂ -- or --(CH₂)₂ --, wherein Q is ##STR22## wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive, wherein R₆₀ is (a) cycloalkyl of 3 to 10 carbon atoms, inclusive, (b) aralkyl of 7 to 12 carbon atoms, inclusive, (c) phenyl, (d) phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, ##STR23## wherein R₁₀ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, and wherein R₁₁ is hydrogen or benzoyl, wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ -- and terminal methyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro, andwherein X is (1) trans--CH═CH-- (2) cis--CH═CH-- (3) --C═C-- or (4) --CH₂ CH₂ --;including the lower alkanoates thereof.
 2. A 5E compound of the formula ##STR24## wherein R₂₀ is ##STR25## wherein L is(1) --(CH₂)_(d) --C(R₂)₂ -- (2) --CH₂ --O--CH₂ --Y-- or (3) --CH₂ CH═CH--wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, being the same or different with the proviso that one R₂ is not methyl when the other is fluoro, and Y is a valence bond, --CH₂ -- or --(CH₂)₂ --, wherein Q is ##STR26## wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive, wherein R₆₀ is (a) cycloalkyl of 3 to 10 carbon atoms, inclusive, (b) aralkyl of 7 to 12 carbon atoms, inclusive, (c) phenyl, (d) phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, ##STR27## wherein R₁₀ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, and wherein R₁₁ is hydrogen or benzoyl, wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ -- and terminal methyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro, and wherein X is (1) trans--CH═CH-- (2) cis--CH═CH-- (3) --C═C-- or (4) --CH₂ CH₂ --; including the lower alkanoates thereof.
 3. A compound according to claim 1 wherein R₂₀ is ##STR28##
 4. A compound according to claim 1 wherein R₂₀ is ##STR29##
 5. A compound according to claim 1 wherein R₂₀ is ##STR30##
 6. A compound according to claim 1 wherein R₂₀ is ##STR31##
 7. A compound acccording to claim 6 wherein L is --(CH₂)_(n) --, n being 3, 4, or 5, wherein Q is ##STR32## wherein R₈ is limited to hydrogen, methyl, or ethyl, and wherein ##STR33## is n-pentyl, 1,1-dimethylpentyl or, 1,1-difluoropentyl.
 8. A compound according to claim 1 wherein R₂₀ is ##STR34##
 9. A compound according to claim 1 wherein R₂₀ is ##STR35##
 10. A compound according to claim 1 wherein R₂₀ is ##STR36##
 11. A compound according to claim 10 wherein L is --(CH₂)_(n) --, n being 3, 4, or 5, wherein Q is ##STR37## wherein R₈ is hydrogen, methyl, or ethyl, and wherein ##STR38## is n-pentyl, 1,1-dimethylpentyl or, 1,1-difluoropentyl.
 12. A compound according to claim 11 wherein X is --C═C--.
 13. A compound according to claim 11 wherein X is --CH₂ CH₂ --.
 14. A compound according to claim 11 wherein X is trans --CH═CH--.
 15. A compound according to claim 14 wherein R₆₀ is ##STR39##
 16. A compound according to claim 14 wherein R₆₀ is ##STR40## wherein R₁₀ and R₁₁ are as defined in claim
 1. 17. (5Z)-9-Deoxy-6,9α-epoxy-methano-Δ⁵ -PGF₁, p-phenylphenacyl ester, a compound according to claim
 16. 